DESCRIPTION: (Applicant's Abstract) This protocol continues implementation of a laboratory model to evaluate pharmacological agents potentially useful in the treatment of cocaine abuse, investigating problems relevant to understanding and reducing uncontrolled cocaine use. It focuses on the smoked route, since crack use is now the major cocaine problem in the United States, and evaluates, within the context of cocaine self-administration, behavioral mechanisms of action of pharmacological agents proposed for treating cocaine dependence. Our approach is to explore several neurotransmitter systems, continuing to collect data on the basic biobehavioral mechanisms of cocaine's actions. Increasing evidence indicates that excitatory and inhibitory amino acid systems play a key role in the modulation of brain function and reward mechanisms. Vigabatrin and lamotrigine act on these modulatory amino acids. We will also test the selective DA autoreceptor antagonist UH 232, which, in laboratory animals, mimics some of cocaine's effects while antagonizing others, and the new antidepressant venlafaxine, which has shown promise in open-label clinical trials. Finally, we will test butorphanol, a partial mu and full kappa opioid receptor agonist, because kappa agonists attenuate many cocaine effects in laboratory animals, and because our laboratory found interesting effects with buprenorphine, the partial mu agonist and kappa antagonist. Our well-characterized laboratory model of cocaine abuse will be used to determine how potential treatment medications alter cocaine craving and the reinforcing, subjective, and cardiovascular effects of self-administered cocaine in non-treatment seeking cocaine users. Two groups of cocaine users will participate: methadone-maintained and non-methadone maintained. These studies will investigate the multiplicity of ways that a medication could enhance cocaine abstinence. The strength of this protocol lies in our utilization of a controlled laboratory setting to examine the interactive effects of potential treatment medications with the many facets of cocaine use, including cocaine "craving." The data collected will suggest more efficacious approaches to treating cocaine abusers.